The objective of this K23 proposal is to enable an early-career investigator to establish an independent research program in translational neuroscience of HIV infection and alcohol use disorders. The K23 studies focus on three high-priority areas within NIAAA's strategic plan: 1) HIV-alcohol interactions; 2) the gut-brain axis; and 3) immune effects of alcohol.8-10 A major contributor to chronic systemic inflammation in HIV is microbial translocation (MT), the abnormal movement of gut products into circulation.11, 12 Heavy alcohol use also is known to cause MT and inflammation.13-15 In HIV, MT and immune activation biomarkers independently predict cognitive impairment, suggesting these processes contribute to neurodegeneration.16-18 Indeed, degeneration of the brain's white matter is a hallmark injury of both HIV infection and heavy alcohol use, independently and in co-occurrence.19-23 White matter degeneration poses a serious health risk for people living with HIV, particularly those who engage in hazardous drinking. Study 1 will investigate whether heavy drinking compounds MT and immune activation in HIV infection and whether these processes predict white matter degeneration over time. Study 1 combines new immune biomarker assays with secondary analysis of neuroimaging and substance use data from a longitudinal study by Brown's Alcohol Research Center on HIV (ARCH; 2P01AA019072). In 180 participants stratified on HIV and heavy drinking status (42 control; 68 HIV only; 34 ETOH only; 36 HIV+ETOH), plasma samples and alcohol use data were collected at baseline, 3, 6, and 12 months. Brain white matter was assessed using diffusion tensor imaging at baseline and 12 months. Using reposited plasma samples, the K23 project will test the hypothesis that specific markers of MT and immune response will predict WM degeneration in heavy drinking, HIV, and their comorbidity. Results will contribute to 1) development of peripheral biomarkers of HIV- and alcohol-related brain damage; 2) guidelines for safer alcohol use specifically in people living with HIV. Study 2 will address critical knowledge gaps on alcohol's acute immune effects by investigating two key contextual factors: 1) alcohol dose and 2) habitual heavy drinking, linked by previous research to intestinal hyperpermeability.13, 24, 25 Study 2 uses a 2 x 3 design with drinking status (light, heavy) as between-subjects factor and beverage condition (placebo, 0.35 g/kg, 0.60 g/kg) as within-subjects factor. Thirty participants (15 light, 15 heavy drinkers) will receive all conditions in randomized, counterbalanced fashion. Change in biomarkers of MT and immune response will be measured. Study 2 with HIV-negative individuals will provide normative data on alcohol-induced immune perturbations to inform planned future studies with HIV-positive individuals. The candidate has assembled a superbly qualified mentor team with expertise in neuroscientific, behavioral, and immunological research on HIV and alcohol use. The K23 training plan will enable the applicant to establish an independent career in translational neuroscience research on HIV-alcohol interactions through mentored training in 1) HIV-specific clinical research; 2) immune processes in HIV and alcohol use; 3) HIV neurobiology of HIV; 4) mechanistic, lab-based alcohol research.

Public Health Relevance

/ PUBLIC HEALTH RELEVANCE This proposal serves public health interests by providing a clinical investigator with interdisciplinary training to conduct translational neuroscience research on HIV infection and alcohol use disorders. Co-occurrence of alcohol use disorders and HIV infection increases risk for adverse and potentially debilitating outcomes. The proposed studies on HIV and alcohol use have potential to identify 1) plasma biomarkers of risk for neurodegeneration; 2) unique and shared pathophysiological mechanisms; 3) guidelines for safer alcohol use, particularly in HIV infection; and 4) specific risk factors for alcohol-related immune compromise.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AA024704-02
Application #
9297178
Study Section
Clinical, Treatment and Health Services Research Review Subcommittee (AA-3)
Program Officer
Regunathan, Soundar
Project Start
2016-06-15
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$175,208
Indirect Cost
$12,978
Name
Brown University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Monnig, Mollie A (2017) Immune activation and neuroinflammation in alcohol use and HIV infection: evidence for shared mechanisms. Am J Drug Alcohol Abuse 43:7-23
Monnig, Mollie A; Kahler, Christopher W; Cioe, Patricia A et al. (2017) Markers of Microbial Translocation and Immune Activation Predict Cognitive Processing Speed in Heavy-Drinking Men Living with HIV. Microorganisms 5:
Merrill, Jennifer E; Treloar, Hayley; Fernandez, Anne C et al. (2016) Latent growth classes of alcohol-related blackouts over the first 2 years of college. Psychol Addict Behav 30:827-837
Monti, Peter M; Monnig, Mollie (2016) Ambivalence and motivational interviewing with adolescents: ensuring that the baby does not get thrown out with the bathwater. Addiction 111:1909-1910
Monnig, Mollie A; Kahler, Christopher W; Cioe, Patricia A et al. (2016) Alcohol use predicts elevation in inflammatory marker soluble CD14 in men living with HIV. AIDS Care 28:1434-40